antiplatelet resistence - significance and how to deal ?

Antiplatelet Drug-resistance in Asian Population

Antiplatelet Drug-resistance in Asian Population

Dr.k.nagendra prasadANTIPLATELET RESISTENCE in ASIAN POPULATION

Topic Outline Concept of antiplatelet resistenceAspirin resistence , types, mechanism Laboratory investigations ManagementClopidogrel resistence , mechanismGenetic polymorphisms importance of testingHigh platelet reactivity testing and its importance in clinical practiceManagement Indian statisticsGuidelinesFuture directions

ANTIPLATELET RESISTENCE in ASIAN POPULATION

Dual antiplatelet therapy combining aspirin and clopidogrel is the standard care for patients who have acute coronary syndromes or are undergoing PCI , according to the current ACC/AHA and ESC guidelines.

However,despite the administration of dual antiplatelet therapy, some patients do develop recurrent cardiovascular ischemic events, with stent thrombosis being the most catastrophic.ANTIPLATELET RESISTENCE in ASIAN POPULATION

This may be secondary to heterogeneity in response of individual patients to each of these drugs.

Varying incidence of aspirin and clopidogrel resistance could be one of the causes of stent thrombosis in post-PCI patients.

The lack of standard definition of resistance as well as its diagnosing modality has hampered the identification and the treatment of this clinical entity. ANTIPLATELET RESISTENCE in ASIAN POPULATION



Aspirin resistance was defined by the presence of at least 2 of the following 3 criteria: 0.5-mg/ml AA-induced platelet aggregation > 20%, 10-mol/l ADP-induced aggregation > 70%, and Verify Now ARU > 550. Aspirin semi-responders are defined as those meeting only one of the criterias.



Classification of aspirin resistanceWeber et al classified aspirin resistance into 3 types based on biochemical and functional in vitrostudies. In aspirin responders, an oral intake of 100 mg/day of aspirin for 5 days resulted in more than 95% inhibition of thromboxane synthesis and also in the inhibition of collagen induced platelet aggregation measured in vitro. In type I resistance, there was no inhibition of either thromboxane synthesis or collagen induced platelet aggregation with oral aspirin intake for 5 days.

However, the in vitro addition of aspirin into the platelet rich plasma showed remarkable change in parameters.

This suggests considerable variation in pharmacokinetics with low dose aspirin, and hence type I resistance is called as pharmacokinetic type resistance.ANTIPLATELET RESISTENCE in ASIAN POPULATION

In type II resistance, both the platelet functions were altered neither by the oral intake of aspirin nor by the in vitro addition of aspirin.

The mechanism of this type of resistance is unclear, but may relate to genetic polymorphism of the enzymatic pathway and its sensitivity to aspirin hence called as pharmacodynamic type resistance.ANTIPLATELET RESISTENCE in ASIAN POPULATION

In type III resistance (pseudoresistance), oral treatment resulted in the inhibition of thromboxane synthesis.

However, this was not accompanied by the expected inhibition of platelet aggregation in response to collagen.

The lack of effect of platelet aggregation in response to collagen despite thromboxane synthesis was not corrected by the addition of aspirin in vitro.

This is labelled as pseudoresistance, since aspirin did exert its putative effect of inhibition of platelet thromboxane synthesis, but failed to alter other important in vitro antiplatelet effects.

This may be due to increased sensitivity of platelets to collagen.ANTIPLATELET RESISTENCE in ASIAN POPULATION

patients with type I resistance may benefit from increasing the dose of aspirin, while type II and III resistance need other antiplatelet drugs like clopidogrel.

But, clinical significance of this classification has not been prospectively tested.ANTIPLATELET RESISTENCE in ASIAN POPULATION





Management of aspirin resistance

Recent observations have demonstrated that the primary cause of aspirin resistance is poor compliance to medication.

When performing a platelet function test assessing for aspirin responsiveness it is imperative to know if the patient is compliant with treatment.

In addition, it is recommended to use platelet function tests specific for COX-1 .


The second most important factor in the management of aspirin-resistant patients is whether the patients are receiving co- medication, especially OTC products such as ibuprofen, which may interfere with COX-1 acetylation.


Some have considered increasing the dose of aspirin in resistant patients.

However, increasing the dose of aspirin has not been associated with an increase in COX-1 inhibition, as assessed by specific assays (Chest 2001;119(suppl):39S 63S).

ADRs may also develop (GI disorders, bleeding, etc.)



CLOPIDOGREL





It is well established that the antiplatelet response to clopidogrel varies widely among patients.

Patients who display little attenuation of platelet reactivity under clopidogrel therapy are recognized as low- or non-responders, or clopidogrel-resistant.


Variable Clopidogrel Response Antiplatelets and Antithrombotics after DES: What Next? ; At 5 DaysUA Patients* (n = 32)Responders47%Low responders32%Nonresponders22%*Received an oral loading dose of 300 mg of clopidogrel followed by 75 mg daily.Gurbel PA, et al. Circulation. 2003;107(23):2908-2913; Lau WC, et al. Circulation. 2004;109(2):166-171.

Individual variability of platelet inhibition after aspirin or clopidogrel administration has been reported. In addition, aspirin and clopidogrel resistance has been reported due to their variable response across patients. In this study by Lau and colleagues, clopidogrel response was compared between UA patients (n = 32) and healthy volunteers (n = 25). Among healthy volunteers, 16% were nonresponders, 12% were low responders, and 72% were responders to clopidogrel administration. Among UA patients, 22% were nonresponders, 32% were low responders, and 47% were responders. In this study, a majority of patients (54%) were either nonresponders or low responders. This study demonstrates the importance of administering alternative antithrombotic therapies to reduce the incidence of thrombotic events that continue to occur for clopidogrel nonresponders and low responders despite oral antiplatelet therapy.

Gurbel PA, et al. Circulation. 2003;107(23):2908-2913; Lau WC, et al. Circulation. 2004;109(2): 166-171; Steinhubl SR, et al. Circulation. 2001;103(21):2572-2578.

Clopidogrel resistance - definitionthe persistent activity of clopidogrel target (i.e. P2Y12 receptors of the platelet) despite an adequate antiplatelet regime.

Clopidogrel non-responsiveness is reported to vary between 4% and 44% among different populations.

In laboratory terms, the definition of clopidogrel resistance varies depending on the different tests used for quantifying residual platelet reactivity and the selection of cut-off values.


More specifically, when light transmittance aggregometry is used, the optimal threshold for defining high residual platelet reactivity is set as a percentage of platelet inhibition lower than 20%, or induced maximal platelet aggregation greater than 50%.

The point of- care assay VerifyNow P2Y12 is most commonly used with a cut-off value that ranges in different research groups from 230-240 platelet reactivity units (PRU). ANTIPLATELET RESISTENCE in ASIAN POPULATION

The prevalence of clopidogrel non- response has been evaluated between 4% and 30% 24 hours after its administration. (J Am Coll Cardiol 2004;43:11271129, Am J Cardiol 2004;93:456458).


Mechanisms of clopidogrel response variability

The mechanisms underlying interindividual variability in response to clopidogrel have not been defined but are probably multifactorial.

J Am Coll Cardiol 2007;49:15051515 Am J Cardiol 2009;103[suppl]: 27A34A Thromb Res 2007;120:311-321



Mechanisms of clopidogrel resistance: PK interactions

Is omeprazole the bad guy? Are all PPIs the bad gang?ANTIPLATELET RESISTENCE in ASIAN POPULATION

Gastric ulcer and duodenal ulcer are known undesirable effects of clopidogrel. This may lead to the use of PPI








STATINSEarly studies suggested a possible negative effect on clopidogrels efficacy from the use of statins, possibly due to the shared CYP3A4 enzymatic pathway between statins and clopidogrel.

However, ample research data, taking advantage of new point-of-care methods for examining platelet aggregation, have clearly ruled out a significant interaction between statins and clopidogrel, concluding that the concomitant use of statins is safe.



Genetic polymorphism exists for CYP2C19 expression.

CYP2C19 alleles are *1, *2, *3, *4, and *7. Allele *1 is normal; *2, *3, and *4 are reduced; and *7 is increased enzymatic activity.

Depending on ethnicity, 3055% of persons harbor a loss-of-function of the CYP2C19 allele (CYP2C19*2).

Compared with noncarriers, CYP2C19*2 carriers treated with clopidogrel had lower levels of active clopidogrel metabolite. ANTIPLATELET RESISTENCE in ASIAN POPULATION


In the GIFT study, the genetic substudy of GRAVITAS, blood samples were tested for 40 polymorphisms, and these correlated with the results of on-treatment VerifyNow P2Y12 assay.

HRPR was increased 11-fold in homozygotes and increased 62% in heterozygotes for the CYP2C19*2 gene, compared with noncarriers.

The study did not find any association of the CYP2C19*17 gain-of-function gene with reduced on-treatment platelet reactivity. ANTIPLATELET RESISTENCE in ASIAN POPULATION

Shetkar et al. in their study of CYP4502C19 polymorphism in 110 Indian patients with coronary artery disease (CAD) shows that 47.23% of the patients are *2 loss-of-function mutation and 35.45% are *7 gain-of-function mutation.

They conclude that CYP2C19 gene polymorphisms are common in Indian population, but loss-of-function mutation status did not affect the clinical outcome of the patients. ANTIPLATELET RESISTENCE in ASIAN POPULATION

Polymorphism also exists in paraoxonase-1 (PON-1), a crucial enzyme responsible for clopidogrel bioactivation, but studies have failed to confirm an association between PON-1 polymorphism and on-clopidogrel platelet reactivity using VerifyNow.ANTIPLATELET RESISTENCE in ASIAN POPULATION






The results of meta-analyses are conflicting.

A report on 9 studies in 9,685 patients undergoing PCI and another involving 10 studies in 11,959 patients, both concluded that reduced-function CYP2C19 alleles expose patients treated with clopidogrel to increased risk of cardiovascular events.

However, 2 recent meta-analyses (not confined to stented patients) showed that although there was an association between CYP2C19 genotype and clopidogrel responsiveness, genotype was not associated with cardiovascular events, with the possible exception of ST in the subgroup of patients undergoing PCI, where ST was associated with CYP2C19 loss-of-function allelesANTIPLATELET RESISTENCE in ASIAN POPULATION






Light transmission and impedance aggregometry assays

Light transmission aggregometry measures optical density of plasma after platelet aggregation with an agonist.

The problem with this test is lack of standardization as to the choice of agonist/s and their concentration.

Furthermore, there is a marked variability in aggregation response to different agonists.

Impedance aggregometry utilizes whole blood instead of plasma and measures electrical impedance instead of light transmission.

This test assesses the role of blood components including leukocytes and clotting factors besides platelets in thrombus formation as a mild electrical current is passed through the whole blood.


Aspirin hyporesponsiveness is defined as more than 10%-20% with light transmittance aggregometry and more than 0 ohms with impedance aggregometry.


VERIFY NOWThe VerifyNow P2Y12 assay is a point-of-care device that uses an automated analyzer with single use, disposable assays.

This assay is simple, accurate and fast in measuring individual response to antiplatelet agents.


VERIFYNOW Point of Care TestIt measures the rate and extent of changes in light transmittance caused by platelet aggregation in a pre-set tube in which whole blood in placed

It thus mimics light transmission aggregometry

Samples containing inhibited platelets will produce low level of light transmittance while samples containing normally functioning platelets will aggregate more rapidly, resulting in higher level of light transmittance




PFA-100assay

This test uses cartridges coated with platelet agonists (either collagen/ADP or collagen/epinephrine).

The time for platelet plug to close the central opening (closing time) is used as a measure of platelet reactivity.

Aspirin resistance is defined as: closing time < 193 s using collagen/epinephrine, and < 121 s using collagen/ADP as agonists.

This test is unfortunately not aspirin-specific. It correlates well with light transmission aggregometry.

TXA2metabolites

Serum TXB2and urinary 11-dehydro-TXB2are metabolites of TXA2

These are COX-1 dependent tests and are not platelet specific and do not necessarily reflect platelet reactivity.

Serum TXB2reflects TXA2formation by endothelial cells and leukocytes in addition to platelets.

Urinary 11-dehydro-TXB2usually requires 24 h urine collection and reflects TXA2formation by renal tissues besides platelets and leukocytes.


The VASP test: A Specific Test to Measure P2Y12 Inhibition

VASP is not phosphorylated at basal state

PGE1 activates VASP phosphorylation

ADP inhhibits VASP phosphorylation via the P2Y12 receptor

Thus high VASP = active form of P2Y12 receptor

Low VASP (high VASP-P) = inhibition of P2Y12 receptor

The recently presented POPULAR study compared the findings of 6 different platelet tests showed a high correlation between the VerifyNow assay and, to a lesser extent, LTA with the plasma level of the active metabolite of clopidogrel was described, suggesting that these may be the preferred laboratory tests for evaluating patient response to clopidogrel.


Clinical significance of in vitro clopidogrel low responsiveness

Several studies have shown that inadequate platelet inhibition leads to adverse clinical outcomes, including recurrent ischemic cardiovascular events, stent thrombosis and periprocedural myocardial infarction.

These studies have been performed in different subgroups of patients undergoing PCI for ST-elevation myocardial infarction (STEMI) or non-STEMI, as well as elective PCI procedures.ANTIPLATELET RESISTENCE in ASIAN POPULATION

Small, randomized studies have demonstrated proof of principle that PFT-guided therapy reduces the risk of cardiovascular events compared with conventional therapy.ANTIPLATELET RESISTENCE in ASIAN POPULATION

Snoep et al. systematically reviewed in the meta-analysis investigating the association between clopidogrel nonresponsiveness and clinical outcome by evidencing an increased risk of clinical recurrences for those with residual platelet reactivity under clopidogrel treatment and he states that laboratory clopidogrel nonresponsiveness is a marker of increased risk of adverse cardiovascular outcomes in patients undergoing PCI with stenting.ANTIPLATELET RESISTENCE in ASIAN POPULATION

The GRAVITAS trial, the first large-scale clinical trial, designed to examine whether adjustment of clopidogrel therapy, on the basis of platelet function testing using a point-of-care assay, safely improves outcome after PCI with drug-eluting stents in clopidogrel resistant patients, did not show any superiority of 150 mg vs. 75 mg of clopidogrelANTIPLATELET RESISTENCE in ASIAN POPULATION






RESULTS - Platelet-function testing with antiplatelet therapy adjustment before and after coronary stenting does not improve clinical outcome as compared with conventional treatment without platelet-function testing. ANTIPLATELET RESISTENCE in ASIAN POPULATION

The results of ARCTIC are consistent with that of GRAVITAS and TRIGGER-PCI in that out-of-hospital event rates in patients undergoing nonurgent PCI are in general low, irrespective of OTR.

The clinical efficacy of PFT in patients undergoing PCI for ACS remains unaddressed by these trials.ANTIPLATELET RESISTENCE in ASIAN POPULATION

Therefore, it is unlikely that functional testing may provide useful information to guide clinical decision making in most individual patients for the prevention of ischemic events.ANTIPLATELET RESISTENCE in ASIAN POPULATION

Rationale for Clinical UseIn the absence of definitive RCTs, the prognostic utility of PFT and genotyping supports an individualized approach to their use in practice.ANTIPLATELET RESISTENCE in ASIAN POPULATION


How to minimize the risk of clopidogrel resistance



In patients undergoing PCI a loading dose of 600 mg clopidogrel was associated with a higher level of platelet inhibition, lower mean post-treatment reactivity to adenosine diphosphate (ADP), and a lower incidence of non-responsiveness when compared to a 300 mg dose.

In the ISAR-CHOICE study, however, there was no additional effect regarding clopidogrel metabolite levels and platelet inhibition between the 600 mg and the 900 mg loading doseANTIPLATELET RESISTENCE in ASIAN POPULATION

The authors concluded that a single dose of clopidogrel higher than 600 mg was not associated with additional significant suppression of platelet function; this was probably due, after analyzing the pharmacokinetic profile and metabolites, to limited clopidogrel absorption.

The 600 mg dose appears to achieve maximum inhibition more rapidly than the 300 mg dose.


The ARMYDA-2 study showed the benefit of 600 mg of clopidogrel when compared with 300 mg of clopidogrel as pretreatment in reducing periprocedural myocardial infarction in patients undergoing PCI.

The utility of increasing the dose of clopidogrel has been further supported by the findings in the ALBION trial.


The OASIS-7 trial randomized 25,087 patients with unstable angina or acute MI to a high dose regimen (600 mg loading dose of clopidogrel, followed by 150 mg per day for 1 week) or the standard regimen (300 mg on the first day followed by 75 mg/day).

At 30 days, the primary endpoint, the combined rate of cardiovascular death, MI, and stroke, occurred similarly in 4.4% of patients on the standard-dose clopidogrel and in 4.2% of patients on the high dose.

However, among the two-thirds of the study patients undergoing PCI, the risk of stent thrombosis was reduced by 30% and the risk of MI was reduced by 22% in the group that received the high dose, compared to the group that received the standard dose.

The highdose group had more major bleeding, but there was no increase in intracerebral or fatal bleeds.

No benefit was found in the group on a higher dose who did not have PCI.ANTIPLATELET RESISTENCE in ASIAN POPULATION


Prasugrel

Prasugrel is a novel thienopyridine introduced for the treatment of acute coronary syndromes.

It is also a prodrug that, after absorption, is converted to its active metabolite, which targets the P2Y12 ADP platelet receptors.

In contrast to clopidogrel, it is mainly metabolized by cytochrome isoenzymes CYP3A and CYP2B6, though there is a lesser contribution from CYP2C9 and CYP2C19.

So CYP2C219 has minimal influence on the formation of prasugrels active metabolite.ANTIPLATELET RESISTENCE in ASIAN POPULATION

Prasugrel quickly demonstrated that it achieves higher and more rapid inhibition of platelet aggregation and a greater reduction of pharmacodynamic non-responders, compared with the standard clopidogrel dose of 75 mg.


Wiviott et al showed, in a randomized crossover study of 201 post-PCI patients, that prasugrel in a loading dose (LD) of 60 mg and 10 mg maintenance dose (MD) achieved higher and more consistent levels of platelet inhibition than clopidogrel at 600 mg LD and 150 mg MD.

The recent ACAPULCO study reinforced this observation by proving prasugrels superiority in platelet inhibition compared to high-dose clopidogrel MD 150 mg or 900 mg LD.

Similar results have been described in clopidogrel resistant patients, with the superiority of prasugrel being more apparent in patients carrying the CYP2C19*2 loss-of-function allele. ANTIPLATELET RESISTENCE in ASIAN POPULATION

In a small though challenging study, Pena et al described clopidogrel responsiveness in 7 patients who presented with stent thrombosis.

The sequential increase of clopidogrel maintenance dose up to 300 mg could not achieve the levels of inhibition achieved by prasugrel.

All 7 patients, 6 of whom had at least one poor-metabolizing allele of CYP2C19, did not respond to 150 mg clopidogrel and 2 of them remained resistant even to a 300 mg clopidogrel maintenance dose, whereas prasugrel achieved adequate platelet inhibition in all of them


In TRITON-TIMI-38 trial, it has shown that both the loading dose and the maintenance dose of prasugrel were superior to clopidogrel for the reduction of ischemic events.

This result emphasizes the importance of maintaining high levels of inhibition of platelet aggregation via P2Y12 receptor inhibition, not only for the prevention of periprocedural ischemic events, but also during long-term follow-up. ANTIPLATELET RESISTENCE in ASIAN POPULATION

TICAGRELORTicagrelor is an oral, direct-acting drug which, like the thienopyridines, targets the ADP receptor P2Y12. However, unlike clopidogrel and prasugrel, the receptor inhibition is reversible.

The PLATO trial compared ticagrelor (180 mg loading dose, 90mg twice daily thereafter) and clopidogrel (300-600 mg loading dose, 75 mg daily thereafter) in 18,624 patients admitted to hospital with an acute coronary syndrome.

The ticagrelor group had a significantly lower occurrence of cardiovascular events, but was associated with a higher rate of major bleeding that was not related to coronary artery bypass grafting.ANTIPLATELET RESISTENCE in ASIAN POPULATION

Recently, the RESPOND Study suggested that ticagrelor therapy might be an appropriate approach to overcome non-responsiveness to clopidogrel in patients with stable coronary artery disease.

Under ticagrelor treatment, platelet reactivity was below the cut-off points previously associated with ischemic in 98% to 100% of patients versus 44% to 76% of patients after clopidogrel therapy.

Furthermore, the antiplatelet effect of ticagrelor was the same in responders and nonresponders



CANGRELORCangrelor, another reversible non-thienopyridine ADP receptor P2Y12 inhibitor, administered intravenously, was assessed in the CHAMPION-PLATFORM and the CHAMPION-PCI trials. Both failed to show superiority compared to clopidogrel.

In vitro, however, the addition of even a sub-therapeutic dose of cangrelor to the platelet-rich plasma of clopidogrel-pretreated patients resulted in an additional reduction of ADP-induced platelet aggregation as measured with the LTA.

Moreover, cangrelor treatment was able to reduce the inter-individual variation observed in clopidogrel-inhibited platelet aggregation.ANTIPLATELET RESISTENCE in ASIAN POPULATION

In CHAMPION PHOENIX trial, cangrelor significantly reduces the rate of ischemic events, including stent thrombosis, during PCI with no significant increase in severe bleeding.

In addition, cangrelor is an intravenous, fast-acting, potent direct-acting P2Y12 antagonist which blocks platelet aggregation more completely than clopidogrel and also does not require hepatic metabolism for activation. ANTIPLATELET RESISTENCE in ASIAN POPULATION



Triple antiplatelet therapy with the addition of cilostazol has been proved in several large-scale studies to be more efficient in preventing adverse clinical events, especially stent thrombosis, without an increase in side effects compared to standard dual antiplatelet therapy.

By laboratory means, cilostazol has also been reported to increase platelet inhibition compared to standard dose clopidogrel in studies using the VerifyNow assay.

Adding cilostazol to standard clopidogrel also appears to be more effective in platelet inhibition, even compared to a high maintenance dose of clopidogrel (150 mg/d), as has been demonstrated by the ACCEL-RESISTANCE study.ANTIPLATELET RESISTENCE in ASIAN POPULATION







Antiplatelet resistence in INDIAN population

The first prospective descriptive study of antiplatelet drug resistance in Indian patients by using VerifyNow test. The study includes total of 200 patients, 87% are males and 13% are females. Platelet function test (PFT) is done in 510 days of the post-PCI. The prevalence of aspirin resistance is 22% in our coronary intervention patients. There is no statistically significant difference of aspirin resistance with gender, age, and diabetes in our patients. The prevalence of clopidogrel resistance is 32.5% in our coronary intervention patient. Large number of female patients are (38%) resistant to clopidogrel (p = 0.001) in our study and this is similar to other international studies. There is no statistically significant difference of clopidogrel resistance with age and diabetes in our patients. ANTIPLATELET RESISTENCE in ASIAN POPULATION



Possibilities To Improve Clinical Usefulness Of PFTs

1.Use of native, instead of citrate-anticoagulated blood.2.Use of a global stimulus - Arterial thrombosis occurs at pathological high shear stresses (>10,000 s1), which create rapid and strong bonds between platelets without prior activation.The shear rate in IMPACT-R is only 1,800 s1(therefore, this test measures platelet adhesion but not aggregation) and in PFA-100 is generously estimated at 5,000 to 6,000 s1.


Platelet interaction with von Willebrand factor, thrombin generation by shear-activated platelets, and shedding of microparticles by shear-activated platelets (a major contributor to thrombin generation) occur only at shear rates exceeding 10,000 s1, and aggregates thus formed are unstable until the shear rate is 20,000 s1.ANTIPLATELET RESISTENCE in ASIAN POPULATION

3. Involvement of platelet-dependent thrombin generation - current point-of-care PFTs most frequently employ citrate-anticoagulated blood, and at the very low plasma calcium levels therein, platelets do not generate thrombin, and consequently, the effect of thrombin on platelets is also attenuated.ANTIPLATELET RESISTENCE in ASIAN POPULATION

4. Clear definition of safety/efficacy thresholds and evaluation of clinical usefulness - PFT should be undertaken not only when practicable, but when it can discriminate sensitively between high- and low-risk patients, can lead to alterations in treatment that improve outcomes and is cost effectiveANTIPLATELET RESISTENCE in ASIAN POPULATION

5.Quality control:- Barriers to adoption of standardized quality assurance for PFTs include:

The need for frequent blood samples, both from many normal donors and affected patients, which maybe practically, clinically, and ethically challenging;

2) Time-delay issues, due to transportation, or with tests employing non-anticoagulated blood.ANTIPLATELET RESISTENCE in ASIAN POPULATION

CURRENT GUIDELINESANTIPLATELET RESISTENCE in ASIAN POPULATION

FUTURE DIRECTION AND CLINICAL CONSIDERATION

A PFT providing both the optimal range of platelet reactivity necessary to prevent thrombotic events, as well as the range to avoid excessive bleeding, would therefore be highly desirable.

PFTs have the most to offer in detecting those who are at highest risk of future cardiovascular events. ANTIPLATELET RESISTENCE in ASIAN POPULATION

We have to assess whether individualization of antiplatelet therapy based on the results of PFT will alter clinical outcome, large randomized clinical trials should be performed in the highest-risk groups [such as ACS patients with high GRACE so that these are adequately powered to detect outcomes.

The optimal timing of PFT is important, especially in ACS. Baseline assessment is often not possible before initiation of treatment, because many, especially those with ST-segment elevation myocardial infarction, will have received DAPT and often a thrombin inhibitor by the time of presentation. Despite testing just before hospital discharge, administration of earlier anticoagulants may still distort PFT results. Assessing patients at 6-week follow-up to guide therapy, after the acute inflammatory response has settled, has the obvious limitation that the first 46 weeks after an ACS is actually the highest thrombotic risk period.

Whether a single result or serial testing is required for ongoing therapy is also unclear. ANTIPLATELET RESISTENCE in ASIAN POPULATION

In the acute setting, dosages can certainly be increased, which, with many agents, can improve PFT results, but there are also many newer agents that reduce MACE in high-risk groups, such as ticagrelor and prasugrel, irrespective of PFT.

The clinical utility of switching drugs on the basis of PFT results in reducing adverse events could not be demonstrated in stable CAD patients, perhaps due to the low event rate after PCI with contemporary DES in this setting.

Whether it is clinically more cost effective to limit prasugrel and ticagrelor to patients with HRPR, or whether it is more efficacious to administer these drugs for all licensed indications without performing PFT, remains to be established.ANTIPLATELET RESISTENCE in ASIAN POPULATION

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antiplatelet resistence - significance and how to deal ?

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